APPLICANT'S DESCRIPTION: There are six fairly disparate aims in this proposal linked by a general concern with how intracellular signaling events in the immune and nervous systems control physiological activities of organisms. Aim is to ask whether the NF-KB transcription factor plays a role in neuronal transmission of signals from synapses. NF-kB is found at synapses and its known control mechanisms make it attractive to think that it could be involved in such activities as long term potentiation. Aim 2 is to use genetic methods to understand activation of NF-kB and of the JNK signaling pathway by tumor necrosis factor and Fas ligand. These pathways have been extensively studied but with conflicting results that genetic methods can resolve. Aim 3 is to try to determine when and how olfactory neurons chose among the 1000 genes encoding potential odor receptors so that one cell expresses only one receptor. This is a problem of gene control in the nervous system that might be analogous to what occurs in the immune system. Aims 4 and 5 relate to the development of improved methods of investigation of mammalian physiology using genetic modifications in mice. Aim 4 is to study the parameters that control homologous integration of transfected DNA in mouse and human cells. Aim 5 is to perfect a method of using lentivirus vectors to bring genes into the mouse male germ cell line, thus doing trangenesis through the sperm. This involves making new better vectors that allow for gene expression. We will also try to extend the work from mice to other species. Aim 6 is to understand how a mouse's immune system avoids reacting with normal tissues of the body and how this system fails in autoimmunity. We will focus here on the role of the IL-2 receptor and the molecules by which it sends intracellular signals.